β-Lactam antibiotics constitute the most important group of antibiotic compounds, with a long history of clinical use. Among this group, the prominent ones are the penicillins and cephalosporins.
Presently, most of the β-lactam antibiotics used are prepared by semi-synthetic methods. These β-lactam antibiotics are obtained by modifying a β-lactam product obtained by fermentation by one or more reactions.
Clavulanic acid and its alkaline metal salts and esters, another type of β-lactam compound than the penicillin and cephalosporin, act as β-lactamase inhibitors, able to enhance the effectiveness of penicillins and cephalosporins. Clavulanic acid has been applied therefore in pharmaceutical compositions to prevent inactivation of β-lactam antibiotics. For example, the antibacterial activity profile of amoxicillin is enhanced by the use of potassium clavulanate as β-lactamase inhibitor. A combination preparation of amoxicillin trihydrate with potassium clavulanate (Augmentin®) is well known.
It is generally known that antibiotic compounds in powder form are not suitable for formulation purposes, because generally these powders perform badly as far as flowability is concerned which causes problems in the manufacturing of final dosage forms, such as tablets. Accurate dosing of the several ingredients is needed to ensure constant end product quality. In case of poor flowabilities, such accurate dosing is difficult to guarantee. Also, the needle shaped crystals, such as of potassium clavulanate, often show a low bulk density. Thus, the contribution of such crystals to the overall volume of the final dosage form is relatively high.
To overcome these problems, often granules of compounds, for example potassium clavulanate with excipients (such as microcrystalline cellulose like Avicel® or silica like Syloid® or Aerosil®) or granules of composition, for example potassium clavulanate with other active ingredients like amoxicillin trihydrate are made before producing the final formulation. Several processes are known to form such granules. For example, in case of wet granulation, potassium clavulanate can be mixed with, for instance, amoxicillin and a binding agent after which the mixture is moistened by a solvent, granulated and bounded. Before tabletting the granules with excipients, the granulates might be sieved. This wet granulation process is economically unattractive, as it uses solvents which must be recovered and/or recycled. It is labour intensive, expensive and time consuming due to the large number of processing steps such as mixing, granulating, sieving, drying etc. Moreover, in case of unstable 1′-lactam compounds such as potassium clavulanate, wet granulation is problematic due to the use of a solvent and high temperature during the drying step of the process.
Another method to granulate poor flowing powders is dry granulation. As an example, the slugging process can be mentioned as described in International patent applications WO 9116893 and WO 9219227. Here, tablets of the poor flowing material with excipients are made and subsequently broken again and sieved to produce granules. Another example of dry granulation is the compaction process as described in International patent application WO 9528927. In this application, a process has been mentioned wherein compacted granules of a β-lactam antibiotic, for example amoxicillin, and a mixture of an active β-lactam antibiotic and a secondary pharmaceutically active agent, for example potassium clavulanate with excipients are made using roller compacting. Subsequently, the roller compacted flakes are milled, resulting in granules which can be mixed with excipients to press the final tablets. An advantage compared to the wet granulation is the absence of solvents. However, the dry granulation is relatively time consuming due to a large number of processing steps. Also, in case of unstable products, a quality risk exists due to locally high temperatures in the process, e.g. due to abrasion. In case the material is hygroscopic, such as potassium clavulanate, another disadvantage is the handling of the dried crystals before and during the granulation process. During this handling, the product might attract water leading to unwanted degradation reactions. Also a major disadvantage of roller compacted products is the relatively large amount of fines which should be removed using sieving techniques to improve the flowability of such products. Furthermore, difficulties one may encounter by using dry granulation are:                a lot of dust is produced during the slugging or roller compaction process and in some cases, for example such as amoxicillin, this dust sticks to the coarser particles and can not be separated by currently applied vibrating sieves,        dust may deteriorate the flow properties of agglomerates,        dust is also responsible for air born β-lactam antibiotics particles which can cause allergic reaction.        
Granules of the active ingredient in the presence of excipients are produced by the process mentioned above. It would be advantageous to have the possibility to produce granules of the pure active ingredient. In that case, the production process can be more flexible and possibly overall less excipients are necessary. Also the production of final dosage forms will be more flexible. In case of hygroscopic substances such as potassium clavulanate, however, it will be difficult to granulate using one of the above processes without the presence of excipients like microcrystalline cellulose or silica, as the latter are known to protect the hygroscopic potassium clavulanate by removing the free water from it and, thus, keeping the water activity of such compositions low. However, in the International patent application WO 9733564 a method has been mentioned in which granules of a pure active ingredient, without the presence of excipients, are made by extrusion. Here, a paste is made of the crystalline powder by adding a liquid wherein the powder is insoluble or slightly soluble. The paste is kneaded then and extruded in a double screwed extruder, after which the granules are dried. The process again is not suitable for unstable products, as locally the temperature in the extruder is high (up to 80° C.). Also, this wet material should be dried at elevated temperatures.
Another method to improve the flowability of needle shaped crystals, especially in the case of potassium clavulanate, is to agglomerate them during crystallisation to the so-called rosette form as described in European patent EP 277008 B1. In this case, a plurality of needle crystals radiate out from a common nucleation point. The rosettes show an increased flowability compared to the needles. However, a large disadvantage of these types of granules is the inclusion of impurities, leading to a decreased chemical quality of the product. Also, the included impurities probably increase the degradation rate of the β-lactam compound, thus resulting in an even worse chemical quality during storage.
The object of the invention is to provide a valuable form of a β-lactam antibiotic compound and a process to prepare such a compound that overcomes most of the above mentioned disadvantages.
Surprisingly, it has been found that novel agglomerates in crystalline form of β-lactam antibiotics in a liquid phase are produced through a crystallisation process when a solution of at least one β-lactam compound in a solvent or in a mixture of solvents under stirring is mixed together with one or more anti-solvents. Preferably, one or both solutions contain water.